Lassa virus (an arenavirus) and Nipah virus (a paramyxovirus) are important emerging pathogens capable of causing lethal disease in humans. Lassa and Nipah viruses are also of concern as possible agents of biowarfare or bioterrorism, with Lassa virus being a category A bioterrorism agent and Nipah virus a category C bioterrorism agent. Despite their increasing importance, little is known about the determinants of virulence of these viruses. A major component of the innate immune response to viruses is the type I interferon (IFN) system, and for this reason, many viruses have developed methods of circumventing the host IFN response. The viral factors which disrupt the IFN-response, IFN-antagonists, are known to be important virulence factors for some viruses, including influenza and herpes viruses. The mechanisms by which the IFN response of the host is blocked vary, and many of the components of the type I IFN system are targeted by at least one known viral encoded IFN-antagonist. Based on data from numerous other viruses, it is very likely that Lassa and Nipah viruses will also encode IFN-antagonists. Because IFN-antagonist proteins are critical for virulence, they are attractive as targets for mutagenesis in the development of live, attenuated vaccines. Further, antiviral drugs that target IFN-antagonists should impair viral replication and might be used to potentiate other antiviral therapies including treatment with interferon. This proposal seeks to (1) clone genes encoding individual Lassa and Nipah virus proteins to permit transient expression; (2) screen individual proteins from Lassa virus and Nipah virus for type I interferon-antagonist function using transfection-based functional assays; and (3) determine the level at which the identified IFN antagonists alter the host interferon response.